Glioma exosomal microRNA-148a-3p promotes tumor angiogenesis through activating the EGFR/MAPK signaling pathway via inhibiting ERRFI1

Cancer Cell International

Shu-Ang Li¹  Ren-De Zhang²  Peng Zhang³  Ti-Kun Shan³  Meng Wang³  Ze-Ming Wang³  Pei-Chao Zhao³  Xue-You Liu³  Zhi-Yun Yu³  Hong-Wei Sun³  Yi Zhao⁴ 

[1] Clinical Systems Biology Laboratories, The First Affiliated Hospital of Zhengzhou University, 450000, Zhengzhou, People’s Republic of China;Department of Medical, The Third Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China;Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East RoadHenan Province, 450052, Zhengzhou, Henan Province, People’s Republic of China;Department of Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, 450000, Zhengzhou, People’s Republic of China;

关键词: Glioma;    Angiogenesis;    Exosomal microRNA-148a-3p;    ERBB receptor feedback inhibitor 1;    EGFR/MAPK pathway;   

DOI  :  10.1186/s12935-020-01566-4

来源: Springer

【 摘 要 】

BackgroundGlioma is the most frequent and lethal primary brain malignancy. Amounting evidence has highlighted the importance of exosomal microRNAs (miRNAs or miRs) in this malignancy. This study aimed to investigate the regulatory role of exosomal miR-148a-3p in glioma.MethodsBioinformatics analysis was firstly used to predict the target genes of miR-148a-3p. Exosomes were then extracted from normal human astrocytes and glioma cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to determine the expression patterns of miR-148a-3p and ERBB receptor feedback inhibitor 1 (ERRFI1). Dual-luciferase reporter gene assay was applied to verify the direct binding between miR-148a-3p and ERRFI1. Cell counting kit-8 and tube formation assays were further conducted to assess the proliferation and angiogenic properties of human umbilical vein endothelial cells (HUVECs) in the co-culture system with exosomes. Lastly, glioma tumor models were established in BALB/c nude mice to study the role of exosomal miR-148a-3p in vivo.ResultsmiR-148a-3p was highly expressed, while ERRFI1 was poorly expressed in glioma. miR-148a-3p was found to be enriched in glioma cells-derived exosomes and could be transferred to HUVECs via exosomes to promote their proliferation and angiogenesis. ERRFI1 was identified as a target gene of miR-148a-3p. In addition, miR-148a-3p activated the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting ERRFI1. In the co-culture system, our data demonstrated that glioma cells-derived exosomal miR-148a-3p down-regulated ERRFI1 and activated the EGFR/MAPK signaling pathway, so as to promote cell proliferation and angiogenesis. In vivo experimentation further demonstrated that this mechanism was responsible for the promotive role of exosomal miR-148a-3p in tumorigenesis and angiogenesis.ConclusionTaken together, glioma-derived exosomal miR-148a-3p promoted tumor angiogenesis through activation of the EGFR/MAPK signaling pathway by ERRFI1 inhibition.

【 授权许可】

CC BY